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关键词： IFN-gamma   sPD-1   BMSCs   lung adenocarcinoma   immune suppression  

摘要： Background Soluble programmed cell death receptor-1 (sPD-1) blocks the PD-1/PD-L1 pathway, reverses tumor immune suppression, and inhibits tumor growth. However, clinical applications are limited by its poor tissue distribution and rapid dispersion. Bone marrow-derived mesenchymal stem cells (BMSCs) are favorable carriers for tumor immunotherapy due to their capacity for external gene introduction and targeted tumor homing. However, they may inadvertently promote tumor growth. Interferon-gamma (IFN-gamma) inhibits BMSC-mediated tumor growth and stimulates antigen-presenting cells to activate T lymphocytes. This study utilizes BMSCs transfected with IFN-gamma as carriers for sPD-1, enabling the targeted homing of sPD-1 to tumor tissues, thereby enhancing the efficacy and sustained stability of *** stable IFN-gamma- and sPD-1-overexpressing BMSCs were successfully constructed by lentiviral transfection. A non-contact co-culture system was established with Lewis and A549 lung adenocarcinoma cells to observe changes in the lung cancer cells after co-culture, using assays including cell migration and invasion experiments, as well as cellular senescence detection. Additionally, a subcutaneous lung adenocarcinoma model was established in C57BL/6J mice for intervention studies. Tumor volume, cellular apoptosis in tumor tissue (assessed by TUNEL assay), peripheral Treg cells (analyzed by flow cytometry), and histopathological markers (evaluated by HE staining and immunohistochemistry) were analyzed. The expression levels of BAX, BCL-2, AKT, PI3K, and PD-L1 were assessed by quantitative PCR and Western *** IFN-gamma- and sPD-1-overexpressing BMSCs exhibited high bioactivity and genetic stability, inhibiting lung adenocarcinoma cell proliferation, accelerating cellular senescence, and reducing migration and invasion. Furthermore, they upregulate Bax expression, downregulate Bcl-2, and promote apoptosis. Additionally, these cells alleviate inflammator

关键词： Infectious disease and host defense   Innate immunity and inflammation   Mucosal immunology  

摘要： To distinguish pathogens from commensals, the intestinal epithelium employs cytosolic innate immune sensors. Activation of the NAIP-NLRC4 inflammasome initiates extrusion of infected intestinal epithelial cells (IEC) upon cytosolic bacterial sensing. We previously reported that activation of the inflammasome in tuft cells, which are primarily known for their role in parasitic infections, leads to the release of prostaglandin D2 (PGD2). We observe that NAIP-NLRC4 inflammasome activation in tuft cells leads to an antibacterial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD2 signaling. A NKp46+ subset of ILC3 expresses the PGD2 receptor CRTH2 and is the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control of Salmonella Typhimurium in the distal small intestine. However, tuft cells in the cecum and colon are dispensable for antibacterial immunity. These data support that intestinal tuft cells can also induce antibacterial responses, possibly in a tissue-specific manner.

关键词： pulmonary function   Tephrosia purpurea   pseudosemiglabrin   iNOS   pancreas   ischemia   reperfusion  

摘要： Ischemia-reperfusion (IR) injury is a major cause of multiple organ failure. The purpose of this study was to look into the role of Tephrosia purpurea (TEP) and its active constituent pseudosemiglabrin (PS) in alleviating severe acute pancreatitis and its associated acute lung injury. We established a rat pancreatic IR model, and the rats were treated with TEP (200 mg/kg and 400 mg/kg) and PS (20 and 40 mg/kg), in addition to the IR control and sham groups. The results showed that the respiratory parameters, including inspiratory time (Ti), expiratory time (Te), duration (Dr), and respiratory rate (RR), were comparable among all groups, while peak inspiratory flow (PIF), forced vital capacity (FVC), and forced expiratory volume at 0.1 s (FEV0.1) were significantly impaired. Notably, PS at 40 mg/kg showed normal PIF, FVC, and FEV0.1/FVC compared to the IR group, indicating an improved lung function. Additionally, TEP and PS showed protective effects on pancreatic and lung tissues compared to the IR control group, with the following effects: alleviating pathological damage;reducing serum levels of trypsinogen activation peptide (TAP), lipase, and amylase;decreasing oxidative stress markers such as MDA and MPO;restoring antioxidant enzyme activity (GPx);suppressing inflammatory markers TNF-alpha, IL-6, and NF-kappa B;downregulating HMGB1 gene in pancreatic tissue;and upregulating the IL-22 gene in lung tissues. In conclusion, the obtained findings demonstrate that oral supplementation of TEP and PS to rats with pancreatic IR alleviates pancreatic and lung injuries by reducing oxidative stress and modulating inflammatory processes, which offers an attractive therapeutic option for severe acute pancreatitis and its associated acute lung injury.

摘要： Interleukin-12 (IL-12) mediates innate and adaptive immune responses and has demonstrated therapeutic anti-tumor activity but clinical development has been hindered by a narrow therapeutic window. We generated a novel IL-12 anchored-drug conjugate by physiochemical linking of murine IL-12 to aluminum hydroxide (alum). The complex was designed to utilize alum as a scaffolding for durable retention of IL-12 within the tumor microenvironment as a strategy to increase the therapeutic window. To better define the systemic PK profile of the anchored IL-12 (mANK-101), a model-based assessment tool was developed to describe the systemic PK profile and downstream signaling factors following intratumoral (IT) injection of mANK-101. When compared to non-anchored IL-12, mANK-101 exhibited a distinct PK profile. Specifically, mANK-101 treatment was associated with a significant 9-fold increase in the systemic terminal volume of distribution (Vd). Furthermore, linear mixed-effects models provided evidence that CD8+ T cell infiltration and increased serum interferon gamma (IFNG) levels were correlated with tumor regression after a single dose of mANK-101. In addition, PK/PD modeling confirmed a link between systemic IL-12 and serum IFNG. The model also suggests that anchored IL-12 drug conjugate is expected to prolong the absorption half-life (115 h vs 8 h for the unanchored drug) with durable local retention and limited systemic absorption. In addition, serum IFNG may be a surrogate marker for drug activity. The PK modeling predictions may also contribute to determining the optimal clinical dose and schedule of ANK-101 and other anchored drug conjugates in patients with solid tumors.

摘要： To elucidate the relationship between circulating cytokines and the prognosis of microsatellite-stable(MSS) colorectal cancer (CRC) patients, we examined the correlation between circulating cytokine levels and tumor immune infiltration microenvironment in this patient population. By conducting a preliminary analysis of the GEO database, we identified five core genes associated with colorectal cancer and further analyzed their impact on immune infiltration. We measured serum cytokine levels and validated the immune infiltration results through immunohistochemical staining of common inflammatory cell markers, including CD3, CD4, CD8, CD163, and FOXP3. Our findings indicate that serum cytokine levels significantly influence immune infiltration in colorectal cancer, particularly IL6 and IFN gamma, which play crucial roles. Specifically, the infiltration of M2-type macrophages and CD8 + T cells is correlated with serum levels of IL6 and IFN gamma. MSS CRC patients with elevated IL6 expression exhibit improved prognosis.

关键词： 中性粒细胞/淋巴细胞比值   血小板/淋巴细胞比值   大动脉炎   心脏瓣膜受累   颈总动脉内-中膜厚度   颈动脉造影强度分级  

摘要： 目的 评价中性粒细胞/淋巴细胞比值（NLR）和血小板/淋巴细胞比值（PLR）联合颈动脉超声造影对大动脉炎（TA）患者心脏损害的评估价值。方法选取空军军医大学第二附属医院风湿免疫科2015年1月～2023年12月收治的大动脉炎患者为研究对象，按照是否发生心脏损害将其分为：心脏损害组（n=43）和无心脏损害组（n=43），收集患者实验室检查、影像学检查及治疗用药进行比较分析，采用Pearson相关系数评价NLR和PLR与Kerr评分、红细胞沉降率（ESR）、C反应蛋白（CRP）、颈总动脉内-中膜厚度（IMT）、颈动脉造影强度分级（CEUS）的关系，采用受试者工作特征曲线（ROC）确定大动脉炎患者心脏损害的界值。结果 心脏损害组的NLR和PLR均显著高于无心脏损害组（2.9±1.0 vs. 2.1±0.8,P<0.01;166±79 vs. 117±51,P<0.01）。心脏损害组IMT、CEUS均较TA无心脏损害组明显升高（2.6±0.6 vs. 1.5±0.4,P<0.01;2.6±0.5 vs 1.6±0.6,P<0.01）。心脏损害组患者NLR水平与CRP呈正相关（r=0.42,P<0.01）,PLR与CRP、CEUS(r=0.34,P<0.05;r=0.35,P<0.05)呈正相关。多因素logistic回归分析结果显示，NLR、IMT、CEUS均为TA并心脏损害的独立危险因素。NLR判断心脏损害的ROC曲线下面积为0.865，其截断点（cut off value）为2.265，灵敏度为69.8%，特异度为90.7%。PLR判断心脏损害的ROC曲线下面积为0.812，其截断点（cut off value）为111.275，灵敏度为76.7%，特异度为79.1%。结论 NLR和PLR联合颈动脉超声造影可用于对大动脉炎患者心脏损害的疾病评估。

关键词： HLA-DR+ regulatory T cells   immune tolerance   systemic lupus erythematosus  

摘要： Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems. A key element in maintaining immune tolerance and preventing autoimmunity is the role of regulatory T cells (Treg cells). Among these, HLA-DR+ Treg cells represent a distinct subset, and their altered expression and functionality in SLE are closely associated with the progression of the disease. This review explores the biological characteristics of HLA-DR+ Treg cells, their mechanisms of action in SLE, as well as their potential and the challenges they pose as therapeutic targets. Methods and results This review offers a comprehensive analysis of the mechanisms by which HLA-DR+ Treg cells regulate immune responses. It highlights their direct interactions with autoreactive T cells and antigen-presenting cells, which contribute to the suppression of autoimmunity. Additionally, the review explores the critical role of these cells in maintaining immune tolerance and their promising potential in the context of antigen-specific immunotherapy. Discussion The potential of HLA-DR+ Treg cells in the treatment of systemic lupus erythematosus (SLE) is considerable, particularly due to their capacity to generate antigen-specific Tregs. The development of Treg-based therapies, including the expansion of both polyclonal and antigen-specific Tregs, is an area of active investigation. Nonetheless, several challenges persist, such as the need to optimize protocols for Treg generation and expansion, ensure the stability of the Treg phenotype, and address potential safety concerns associated with cellular *** research is essential to fully harness the potential of HLA-DR+ Treg cells in the treatment of SLE and other autoimmune diseases.

关键词： severe obesity   RNA-seq   transcriptome   proteome   multi-omics   understudied population   obesity   adiposity  

摘要： Polygenic severe obesity (body mass index [BMI] >= 40 kg/m(2)) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA sequencing analysis identified 124 genes significantly differentially expressed between severe obesity cases (BMI >= 40 kg/m(2)) and controls (BMI <25 kg/m(2));33% replicated in an independent sample from the same population. Our integrative approach identified inflammatory genes, including IL4R, ZNF438, and LILRA5. Several genes displayed transcriptomic effects on severe obesity in subcutaneous adipose tissue. We further showed that the genetic regulation of these genes is associated with several traits in a large biobank, including bone fractures, obstructive sleep apnea, and hyperaldosteronism, illuminating potential risk mechanisms. Our findings furnish a molecular architecture of the severe obesity phenotype across multiple molecular domains.

关键词： 抗体   抗原   蛋白质语言模型   卷积神经网络   双向长短时记忆网络  

摘要： 抗体与抗原之间的相互作用是免疫系统识别和对抗病原体的核心机制，同时也是抗体药物设计的关键环节。近年来涌现出一些基于深度学习的方法来提升抗体抗原相互作用预测的效率和精度。为进一步提高预测性能，本文提出了一种新型深度学习模型CBAAI。该模型整合了卷积神经网络（CNN）、双向长短时记忆网络（BiLSTM）以及残差网络的优势。具体而言，CBAAI 首先将抗体和抗原序列输入蛋白质语言模型，提取高质量的序列特征嵌入。然后，通过基于CNN和 BiLSTM 的残差单元对序列特征进行融合，以构建抗体抗原相互作用预测模型。在HIV和SARS-CoV-2 两个独立测试集上的实验结果表明，与当前的主流方法相比，CBAAI 在多个评估指标上均取得了显著的性能提升。

关键词： 和解清热消积汤   上呼吸道感染   T淋巴细胞   免疫球蛋白   免疫应答  

摘要： 目的 探究和解清热消积汤对小儿肺脾气虚夹热夹滞型反复上呼吸道感染的临床疗效。方法 选取2023年1月-2023年12月于我院儿科就诊的肺脾气虚夹热夹滞型反复上呼吸道感染患儿72例，采用随机分组法分为观察组及对照组各36例，其中对照组采用西药治疗，观察组在对照组基础上采用和解清热消积汤治疗，比较治疗一周后临床症状改善程度及不良反应，于治疗前及治疗一周后比较两组患儿中医证候积分、T淋巴细胞亚群水平[T淋巴细胞分化群3(Cluster of differentiation 3+，CD3+)、T淋巴细胞分化群4(Cluster of differentiation 4+，CD4+)、T淋巴细胞分化群8(Cluster of differentiation 8+，CD8+)、T淋巴细胞分化群4/T淋巴细胞分化群8(CD4+/CD8+)]、免疫球蛋白[免疫球蛋白A（Immunoglobulin A，IgA）、免疫球蛋白M（Immunoglobulin M，IgM）、免疫球蛋白G（Immunoglobulin G，IgG）]水平、Th1/Th2免疫应答指标[白细胞介素-2（Interleukin-2，IL-2）、干扰素γ（Interferon-gamma，IFN-γ）、白细胞介素-4（Interleukin-4，IL-4）、白细胞介素-10（Interleukin-10，IL-10）]水平差异变化。结果 治疗一周后，两组患儿临床症状改善时间、中医证候积分、CD8+、IL-4、IL-10水平显著低于同期对照组（P<0.05）；T淋巴细胞亚群(CD3+、CD4+、CD4+/CD8+)、免疫球蛋白、Th1/Th2免疫应答指标（IL-2、IFN-γ）水平明显高于同期对照组（P<0.05）。两组患儿均无明显不良反应。结论 和解清热消积汤能够有效调节肺脾气虚夹热夹滞型反复上呼吸道感染患儿机体免疫功能，增强机体免疫力，减轻其临床症状，加快疾病恢复进程，临床疗效良好。